Studies on pyrimidine derivatives. XXXIX. Site-selectivity in the reaction of 5-substituted and 4,5-disubstituted pyrimidine N-oxides with trimethylsilyl cyanide.

Abstract

The site-selectivity in the modified Reissert-Henze reaction of 5-substituted, and 4,5-disubstituted pyrimidine 1-oxides with trimethylsilyl cyanide was examined. The reaction of 5-substituted 4-methoxypyrimidine 1-oxides with trimethylsilyl cyanide gave exclusively 2-pyrimidinecarbonitriles in good yields without exception. On the other hand, the other 5-substituted and 4,5-disubstituted pyrimidine 1-oxides gave mainly 6-pyrimidinecarbonitriles.Keywords site-selectivity; pyrimidine N-oxide; trimethylsilyl cyanide; Reissert-Henze reaction; pyrimidinecarbonitrile As reported previously, when pyrimidine 1-oxides substituted with an electron-donating group at position 4 were treated with trimethylsilyl cyanide (TMSCN),2) significant siteselectivity due to substituent effects was observed, and 2-pyrimidinecarbonitriles were formed predominantly.3) For example, the reaction of 4-methylpyrimidine 1-oxide with TMSCN gave 4-methyl-2-pyrimidinecarbonitrile as a sole product, while the reaction of pyrimidine 1-oxide itself under the same conditions gave a 2 : 3 mixture of 4-pyrimidinecarbonitrile and 2-pyrimidinecarbonitrile.On the other hand, the reaction of 3-halopyridine 1-oxides with TMSCN was reported to give 3-halo-2-pyridinecarbonitriles selectively.4) Similar results were observed in the reaction of 3-methoxy-and 3-dimethylaminopyridine 1-oxides with the same reagent. The orienting effect of these substituents on the cyanation has been explained by assuming a cyclic mechanism due to the interaction between the substituents and TMSCN.4) Our interest was next focussed on the comparison of these two different orienting effects in the same ring system. The present paper deals with the reaction of 4,5-disubstituted pyrimidine 1-oxides with TMSCN, because such pyrimidine 1-oxides are considered to be easily available substrates having favorable structures for the comparison of these effects in a single molecule.In advance of the main investigation, the reaction of 5-substituted pyrimidine 1-oxides with TMSCN was carried out. When 5-phenyl-(1a), 5-methyl-(1b), 5-methoxy-(1c), 5-chloro-(1d), and 5-bromopyrimidine 1-oxide (1e) were treated with TMSCN under the reported conditions,3m the corresponding 5-substituted 4-pyrimidinecarbonitriles (5'a-e) were formed predominantly. The formation ratio of the isomers determined by gaschromatographic analysis are listed in Table I. Based on the results described above, it is concluded that the reaction of 5-substituted pyrimidine 1-oxides tends to give 4-pyrimidinecarbonitriles, although the orienting effect due to the interaction between 5-substituents and TMSCN is not sharply observed as in the case of 3-substituted pyridine 1-oxides.

One-Step Conversion of Azine N-Oxides to α-1,2,4-Triazolo-, 1,2,3-Triazolo, Imidazolo-, and Pyrazoloheteroarenes

“…Isoquinoline N -oxide yielded a mixture of 1- and 3-substituted products, including the 1-tosylate, with reagent A and a complex mixture with reagent B . Contrary to expectations, reactions with pyrimidine N -oxide (entry 10) yielded product mixtures heavily favoring substitution in the 2- rather than the 4-position . Reaction of A with 7-azaindole N -oxide (entry 12) gave a mixture of 47 (10%) and two products of substitution, one with a free N−H ( 46 , 20%) as well as the N -tosyl product ( 45 , 31%), suggesting activation of the N -oxide is competitive with tosylation of the azaindole nitrogen.…”

Structure−Activity Studies for a Novel Series of Tricyclic Substituted Hexahydrobenz[e]isoindole α1A Adrenoceptor Antagonists as Potential Agents for the Symptomatic Treatment of Benign Prostatic Hyperplasia (BPH)

“…3-[2-( cis -6-Methoxy-2,3,3a,4,5,9b-hexahydro-[1 H ]-benz[ e ]isoindol-2-yl)ethyl]-thieno[3,2- d :4 ,5- d ]dipyrimidine-2,4(1 H ,3 H )-dione (50). 5-Bromo-4-cyanopyrimidine (2.10 g, 11.4 mmol) was treated with ethyl thioglycolate (1.38 g, 11.5 mmol) and Na 2 CO 3 (1.21 g, 11.4 mmol) in EtOH (36 mL) as described for example 49 to yield 1.10 g (43%) of ethyl 3-aminothieno[3,2- d ]pyrimidine-2-carboxylate, mp 139−141 °C. 1 H NMR (CDCl 3 ) δ 1.42 (t, 3H), 4.41 (q, 2H), 6.17 (br s, 2H), 9.19 (s, 1H), 9.20 (s, 1H).…”

Scalable Synthesis of 4-Substituted 5-Bromo-6-methylpyrimidines

“…This route is a significant improvement over a previously published synthesis. 5 Besides being a valuable monomer, the nitrile provides a convenient handle for further synthetic elaboration into such moieties as tetrazoles, 6 carboxylic acids, 7 isoxazoles, 8 Studies focused on directly conjugating carbon nucleophiles in a chemoselective fashion with 6 are currently underway. Related analogue 5-bromo-4,6-dimethylpyrimidine (5) was synthesized in bulk by treating 4,6-dimethylpyrimidine (13) with bromine in ethanol (Scheme 5), whereupon after several hours at room temperature, the desired 5-bromopyrimidine 5 precipitated from solution in high purity (>98%) as its HBr salt, thus negating the need for further purification.…”